Neurovascular Coupling During Cortical Spreading Depolarization and –Depression

Østergaard, Leif; Dreier, Jens P.; Hadjikhani, Nouchine; Jespersen, Sune Nørhøj; Dirnagl, Ulrich; Dalkara, Turgay

doi:10.1161/strokeaha.114.008077

Cited by 42 publications

(33 citation statements)

References 55 publications

(115 reference statements)

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“…Finally, extreme constriction could be due to abnormal recruitment of the neurovascular signaling pathways that couple flow levels to local neural activity (31, 99). Pathological bursting, excitotoxicity, or spreading depolarization at the time of trauma may drive abnormal recruitment of constriction (100–102), and there is evidence of this phenomenon in severe human injury (103). Interestingly, constriction due to spreading depolarization has also been seen to coincide with capillary stalling (101, 102)…”

Section: Discussionmentioning

confidence: 99%

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

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Keywords: traumatic brain injury, mouse, weight drop injury, cerebral blood flow, capillary, in 21 vivo, laser speckle contrast imaging, optical coherence tomography, two-photon imaging 22 23 24 Acknowledgments: We thank Tim Otchy, Jennifer Morgan, and members of the Davison and 25 Boas laboratories for comments and discussion. This work was supported by Boston University 26 startup funds.Abstract 30 Traumatic brain injury (TBI) is a major source of cognitive deficits affecting millions annually. The 31 bulk of human injuries are mild, causing little or no macroscopic damage to neural tissue, yet can 32 still lead to long-term neuropathology manifesting months or years later. Although the cellular 33 stressors that ultimately lead to chronic pathology are poorly defined, one notable candidate is 34 metabolic stress due to reduced cerebral blood flow (CBF), which is common to many forms of 35 TBI. Here we used high-resolution in vivo intracranial imaging in a rodent injury model to 36 characterize deficits in the cortical microcirculation during both acute and chronic phases after 37 mild TBI. We found that CBF dropped precipitously during immediate post-injury periods, 38 decreasing to less than half of baseline levels within minutes and remaining suppressed for 1.5-39 2 hours. Repeated time-lapse imaging of the cortical microvasculature revealed further striking 40 flow deficits in the capillary network, where 18% of vessels were completely occluded for 41 extended periods after injury, and an additional >50% showed substantial stoppages. Decreased 42 CBF was paralleled by extensive vasoconstriction that is likely to contribute to loss of flow. Our 43 data indicate a major role for vascular dysfunction in even mild forms of TBI, and suggest that 44 acute post-injury periods may be key therapeutic windows for interventions that restore flow 45 and mitigate metabolic stress. 46 47 88 dysfunction across the cortical microvasculature, where a large fraction of individual capillaries 89were occluded for periods of minutes or longer, leading to localized regions with complete loss 90 5 of perfusion. CBF largely returned to normal by 3 hours after injury and showed no measurable 91 deficits when tracked until 3 weeks. Reduced CBF was paralleled by pronounced 92 vasoconstriction, identifying a potential mechanism contributing to disrupted flow. This rapid 93 and extensive vascular dysfunction highlights the importance of immediate post-injury periods 94 for delivering interventions, and suggests that relieving vasoconstriction will be a promising 95 avenue for countering the effects of mild injury. 96 97 Methods 98 99 Animals and surgical procedures 100 All experiments were performed in 2-5 month-old male and female C57BL6/J mice in accordance 101 with guidelines of the Boston University Institutional Animal Care and Use Committee. Animals 102 were group housed on a 12-hour light/dark cycle with ad libitum access to food and water. 103 Chronic cranial windows were implanted using standard procedures (30, 31). Brie...

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Section: Discussionmentioning

confidence: 99%

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Witkowski¹,

Erdener²,

Kılıç³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…9,79 In view of the current concepts on NaKA and Ca 2þ regulation, the present findings support the hypothesis that (a) elevated [ Conclusion SI is clinically important in different conditions including aSAH [5][6][7]82 but exceedingly complex, involving dysregulation in all cell types of the neurovascular unit 8,30 and all segments of the vascular tree from large arteries 83 up to capillaries. 84 The physiological level of NO shows preventive effect, pursuing a defense-indepth strategy that fights the occurrence of SD in the first place, and second, aims at maintaining the normal hyperemic response in the case that SD occurs. This supports the therapeutic approach in patients with aSAH to sustain the basal level of NO.…”

Section: Discussionmentioning

confidence: 99%

A role of the sodium pump in spreading ischemia in rats

Major

Petzold

Reiffurth

et al. 2016

J Cereb Blood Flow Metab

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In rats, spreading depolarization induces vasodilation/hyperemia in naïve tissue but the inverse response when artificial cerebrospinal fluid is topically applied to the brain containing (a) a nitric oxide-lowering agent and (b) elevated K þ . The inverse response is characterized by severe vasoconstriction/ischemia. The perfusion deficit runs together with the depolarization in the tissue (¼spreading ischemia). Here, we found in male Wistar rats that pre-treatment with artificial cerebrospinal fluid containing elevated K þ in vivo led to a selective decline in a 2 /a 3 Na þ /K þ -ATPase activity, determined spectrophotometrically ex vivo. Moreover, spreading ischemia, recorded with laser-Doppler flowmetry and electrocorticography, resulted from artificial cerebrospinal fluid containing a nitric oxide-lowering agent in combination with the Na þ /K þ -ATPase inhibitor ouabain at a concentration selectively inhibiting a 2 /a 3 activity. Decline in a 2 /a 3 activity results in increased Ca 2þ uptake by internal stores of astrocytes, vascular myocytes, and pericytes since Ca 2þ outflux via plasmalemmal Na þ /Ca 2þ -exchanger declines. Augmented Ca 2þ mobilization from internal stores during spreading depolarization might enhance vasoconstriction, thus, contributing to spreading ischemia. Accordingly, spreading ischemia was significantly shortened when intracellular Ca 2þ stores were emptied by pre-treatment with thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca 2þ -ATPase (SERCA). These findings might have relevance for clinical conditions, in which spreading ischemia occurs such as delayed cerebral ischemia after subarachnoid hemorrhage.

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“…; Ostergaard et al . ). Astrogliosis‐induced changes in NVC deserve further attention in this regard.…”

Section: Introductionmentioning

confidence: 97%

Binaural blood flow control by astrocytes: listening to synapses and the vasculature

Mishra

2016

The Journal of Physiology

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Astrocytes are the most common glial cells in the brain with fine processes and endfeet that intimately contact both neuronal synapses and the cerebral vasculature. They play an important role in mediating neurovascular coupling (NVC) via several astrocytic Ca -dependent signalling pathways such as K release through B channels, and the production and release of arachidonic acid metabolites. They are also involved in maintaining the resting tone of the cerebral vessels by releasing ATP and COX-1 derivatives. Evidence also supports a role for astrocytes in maintaining blood pressure-dependent change in cerebrovascular tone, and perhaps also in blood vessel-to-neuron signalling as posited by the 'hemo-neural hypothesis'. Thus, astrocytes are emerging as new stars in preserving the intricate balance between the high energy demand of active neurons and the supply of oxygen and nutrients from the blood by maintaining both resting blood flow and activity-evoked changes therein. Following neuropathology, astrocytes become reactive and many of their key signalling mechanisms are altered, including those involved in NVC. Furthermore, as they can respond to changes in vascular pressure, cardiovascular diseases might exert previously unknown effects on the central nervous system by altering astrocyte function. This review discusses the role of astrocytes in neurovascular signalling in both physiology and pathology, and the impact of these findings on understanding BOLD-fMRI signals.

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Neurovascular Coupling During Cortical Spreading Depolarization and –Depression

Cited by 42 publications

References 55 publications

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

Rapid disruption of the cortical microcirculation after mild traumatic brain injury

A role of the sodium pump in spreading ischemia in rats

Binaural blood flow control by astrocytes: listening to synapses and the vasculature

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